Dose of Early Therapeutic Mobility: Does Type and Frequency of Activity Matter? Abstract Early therapeutic mobility (ETM) activity has been recommended to facilitate recovery and improve outcomes, particularly for the one million survivors of critical illness. The effective dose (i.e., type, frequency and duration) of ETM activity is not known and there are limited reports about the application and effects of ETM in mechanically ventilated intensive care unit (ICU) patients. Three inflammatory biomarkers, interleukin (IL)-6, IL-10 and C-reactive protein, are potentially altered by a single episode of ETM activity. Systemic markers of physical health (i.e., vital signs, delirium, muscle strength, ventilator associated pneumonia, and length of time mechanically ventilated) may also be positively influenced by ETM. The primary aim of this interdisciplinary study is to compare the immediate effects of single and twice daily episodes of ETM activity and the effects of low and moderate types of ETM activity on molecular biomarkers of inflammation and systemic markers of physical health in mechanically ventilated adults. The secondary aim is to explore approaches and effect sizes for future multi-site trials. This is a quasi-experimental design, using repeated measures;subjects will be randomized to receive either one or two episodes of ETM activity daily for 3 days, then weekly when length of stay exceeds 3 days. Type of ETM activity will be determined by patient condition and frequency will be randomized. The primary research questions are: (1a) What are the differences between the frequency (once versus twice daily) of ETM activities on inflammatory biomarkers: interleukin (IL)-6, IL-10 and C-reactive protein (CRP)? (1b) What are the differences between the type (low or moderate) of ETM activities on inflammatory biomarkers: IL-6, IL-10 and CRP? (2a) What are the differences between frequency of ETM activities on systemic markers of physical health: vital signs, delirium, muscle strength, ventilator-associated pneumonia and days of mechanical ventilation? (2b) What are the differences between type of ETM activities on systemic markers of physical health: vital signs, delirium, muscle strength, ventilator-associated pneumonia and duration of mechanical ventilation? Data will be collected for a maximum of 3 contiguous days in ICU patients who are mechanically ventilated for >24 hours, then weekly to examine short-term patient responses to ETM activities in this preliminary study. Daily episodes of activity will be provided by a study interventionist. Type of activity will be determined by patient condition and frequency of activity will be randomized as once or twice daily each day the patient is in the ICU. Repeated measures MANCOVA and ANCOVA will be used to answer the research questions. This collaborative study evaluates a biobehavioral methodology within an interdisciplinary team consistent with the biobehavioral methods to improve outcome research (PA-07-008) and the mission of the National Institute of Nursing Research to improve treatments and health based on evidence. Public Health Relevance: Early therapeutic mobility may interrupt pathologic systemic inflammation. This innovative study will examine the impact of ETM activity on inflammatory biomarkers in adults receiving mechanical ventilation. It investigates for the first time the affect of passive range of motion on recovery in patients in the intensive care unit. Molecular and systemic markers of health may be used to guide the bedside clinician in implementing and progressing mobility therapy. This study is a preliminary step in the investigation of the optimal "dose" of ETM activity in mechanically ventilated patients and has the potential to improve recovery from critical illness.